Localized delivery of therapeutics via biodegradable nanoparticles often provides advantages over systemic drug administration, including reduced systemic side effects and controlled drug levels at target sites. However, controlled drug delivery at mucosal surfaces is generally limited by the presence of the protective mucus layer.
Mucus, the first line of defense covering all mucosal surfaces, is an adhesive, viscoelastic gel that effectively prevents particulates from reaching the epithelial surface if they are larger than, and/or adhere to, the mucus mesh (Cone, Mucosal Immunology, 3rd Edition 2005, 49-72; Cone, Adv Drug Deliv Rev, 2009, 61, 75-85; Lai et al., Proc Natl Acad Sci USA, 2007, 104, 1482-1487; Olmsted et al., Biophys J, 2001, 81, 1930-1937; Ensign, Sci Transl Med, 2012, 4, 138ra179).
The mucosa consists of an epithelium, formed of one or more layers of epithelial cells and an underlying lamina propria of loose connective tissue. The mucous membranes ensure that the underlying lamina propria of connective tissue remains moist by secreting mucus. Mucus efficiently traps foreign particles and particulates by both steric and adhesive mechanisms, facilitating rapid clearance and hindering drug delivery.
The adhesion of drug particles and/or delivery vehicles to mucus can significantly decrease the efficiency of drug delivery. For example, most therapeutics delivered locally to mucosal surfaces suffer from poor retention and distribution as a result of mucus turnover. Thus, “mucoadhesion” has been shown to result in limited distribution of drugs delivered directly to the mucosa over vaginal, lung, and colorectal tissues (Ensign, Sci Transl Med, 2012, 4, 138ra179; Ensign et al., Biomaterials, 2013, 34, 6922-6929; Suk et al., J Control Release, 2014, 178, 8-17; Maisel et al., J Control Release, 2015, 10, 197, 48-57, Epub 2014 Nov. 4), which severely limits the efficacy of these drugs.
For drug or gene delivery applications, therapeutic particles must be able to achieve uniform distribution over the mucosal surface of interest and cross the mucus barrier efficiently to avoid rapid mucus clearance, ensuring effective delivery of their therapeutic payloads to underlying cells (das Neves J & Bahia M F, Int J Pharm, 2006, 318, 1-14; Lai et al., Adv Drug Deliver Rev, 2009, 61, 158-171; Ensign et al., Sc. Transl Med, 2012, 4, 138ra179, 1-10; Eyles et al., J Pharm Pharmacol, 1995, 47, 561-565).
Many factors are known to contribute to the mucoadhesive characteristics of nanoparticles (Lai et al., Proc Natl Acad Sci USA, 2007, 104, 1482-1487; Ensign, Sci Transl Med, 2012, 4, 138ra179). Typically, positively charged surfaces, and/or uncoated hydrophobic surfaces are considered to be highly mucoadhesive. PEG has been used to enhance mucoadhesion (Peppas, J Biomater Sci Polym Ed, 1998, 9, 535-542; Peppas et al., Adv Drug Deliv Rev, 2004, 56, 1675-1687; Peppas et al., Biomaterials, 1996, 17, 1553-1561; Peppas et al., Biomater Sci Polym Ed, 2009, 20, 1-20; Sahlin et al., J Biomater Sci Polym Ed, 1997, 8, 421-436; Huang et al., J Coontro Release, 2000, 65, 63-71; Smart et al., Adv Drug Deliv Rev, 2005, 57, 1556-1568; Serra et al., Eur J Pharm Biopharm, 2006, 63, 11-18). High-molecular weight PEG has been described as acting as a mucoadhesive “glue” that interpenetrates and entangles with mucin fibers (Peppas, J Biomater Sci Polym Ed, 1998, 9, 535-542; Peppas & Sahlin, Biomaterials, 1996, 17, 1553-1561) or forms hydrogen bonds to the carbohydrate regions of the mucin fibers (Deascentiis et al., J Control Release, 1995, 33, 197-201; Peppas, J Biomater Sci Polym Ed, 1998, 9, 535-542; Peppas & Huang, Adv Drug Deliv Rev, 2004, 56, 1675-1687; Peppas & Sahlin, Biomaterials, 1996, 17, 1553-1561; Peppas et al., J Biomater Sci Polym Ed, 2009, 20, 1-20; Martini et al., International Journal of Pharmaceutics, 1995, 113, 223-229; Sahlin & Peppas, J Biomater Sci Polym Ed, 1997, 8, 421-436; Huang et al., J Control Release, 2000, 65, 63-71). PEG of a molecular weight as high as 10 kDa has been reported to have inconsistent influences on the mucus penetration of coated particles. For example, 10 kDa PEG of a comparable coating density as 2 kDa PEG (e.g., PEG 2 kDa) either caused mucoadhesion (Wang et al., Angew Chem Int Ed Engl, 2008, 47, 9726-9729) or exhibited similar mucoadhesive capacity as non-coated particles (Deascentiis et al., J Control Release, 1995, 33, 197-201). In another example, PLGA-PEG nanoparticles formed using an emulsion method allowed PEG to partition to the particle surface during the slow hardening process, resulting in a sufficiently high surface density for up to 10 kDa PEG for mucus penetrating coatings (Xu et al., J Control Release, 2013, 170, 279-286).
Other studies established that nanoparticles densely coated with low-molecular weight hydrophilic polymers, such PEG 1 kD, are able to penetrate mucus barriers to reach and uniformly coat epithelial surfaces (Lai et al., Proc Natl Acad Sci USA, 2007, 104, 1482-1487; Ensign, Sci Transl Med, 2012, 4, 138ra179; Suk et al., J Control Release, 2014, 178, 8-17; Maisel et al., J Control Release, 2015, 10, 197, 48-57, Epub 2014 Nov. 4). In addition, these mucus penetrating nanoparticles (MPP) are retained for longer periods of time in the cervicovaginal and respiratory tracts compared to mucoadhesive particulates (Ensign, Sci Transl Med, 2012, 4, 138ra179; Suk et al., J Control Release, 2014, 178, 8-17), indicating that MPP may be more suitable for distributing drugs to the entire epithelial surface and providing prolonged drug retention.
There exists a need for new methods of preparing mucus-penetrating particles which can encapsulate a wide range of drugs into the nanoparticles without a decrease in the mucus penetrating properties as described above. There is a similar need for formulations which are administered via injection.
Therefore, it is an object of the invention to provide methods of preparing particles, and the resulting particles, which can encapsulate a wide range of drugs into the biodegradable nanoparticles without a decrease in the mucus penetrating properties.
It is another object of the invention to provide particles, such as nanoparticles and microparticles, with high drug loading and a dense coating of a surface-altering material to provide effective drug delivery via a variety of routes of administration including via mucosal surfaces.